by Ayisha Sharma in London.

Santhera Pharmaceuticals’ vamorolone for Duchenne muscular dystrophy (DMD) has experts cautious on how an uncontrolled diet in the Phase IIb VISION-DMD trial will impact the potential trustworthiness of data.

The Phase IIb (NCT03439670) protocol cites body size measured by the BMI-Z score across both the treatment and control arms as a safety measure. But the results could be confounded by the different degree to which parents control individual patients’ diets. Potential results would have been more trustworthy if patients had been placed on a high-protein, low-fat diet with a set calorie restriction. But given the trial enrols patients between the ages of 4 and 7, expected calorie intake would be different for individual patients anyway, so a lack of diet control does not necessarily entail undependable results.

Nonetheless, the BMI-Z has a clear rationale in comparing weight gain between Santhera Pharmaceuticals’ vamorolone and prednisone, as this is one of the steroid’s key early side effects. Although cites the BMI-Z score as a coprimary measure, a company spokesperson said this not the case but it is an important safety outcome.

Stronger treatment efficacy appears to be correlated with higher doses, which in turn bring safety concerns, rendering vamorolone’s risk-benefit profile akin to that of a steroid, just with lower intensity. While Phase IIa extension results in the coprimary efficacy endpoint of muscle function measured by time-to-stand (TTSTAND) velocity, which is the Phase IIb primary efficacy outcome, seem meaningful, most experts said the earlier study’s 24-week timeframe means it is still too early to comment definitively on clinical significance. The Phase IIb primary outcome measures are also studied over 24 weeks, according to

Although Santhera Pharmaceuticals’ vamorolone’s early safety signals are higher in number when compared with PTC Therapeutics’ steroid Emflaza (deflazacort), the former is still preferable when one considers the long-term safety concerns of steroids such as growth issues and bone fragility.

VISION-DMD results are expected in 4Q20, followed by an NDA filing in 1Q21 according to a 12 June company presentation. Santhera has a market cap of $101.5m. Vamorolone is expected to attain peak sales of $423.8m, according to an analyst report.

BMI-Z score endpoint for Santhera drug vamorolone likely confounded by protocol

As regards the 120-patient, placebo- and active-controlled, double-blind Phase IIb, it is important to control patient diets across the vamorolone and prednisone control arms in order to ensure a fair comparison, said Lee Sweeney, PhD, director, Myology Institute, University of Florida College of Medicine, Gainesville. As each group will likely have relatively small numbers, if some parents are laxer on their children’s food intake and others are more careful about diets, results will become confounded and impossible to compare, he explained.

Patients in the trial will be randomised 1:1:1:1 (vamorolone 2.0 mg/kg/day: vamorolone 6.0 mg/kg/day: prednisone 0.75 mg/kg/day: placebo), according to However, other than the instruction to take at least 8g of fat with the daily dose of treatment, there are no other food or drink restrictions on the study, according to the study protocol.

Specifically, the calorie intake should have been capped to ensure trustworthy Phase IIb results, said Jacques Tremblay, PhD, professor, Department of Molecular Medicine, Université Laval, Québec, Canada. A high-protein, low-fat diet with a calorie restriction would be the ideal method to satisfactorily control potential weight gain on the trial, Sweeney explained. While there may have been issues with compliance even if dietary controls had been part of protocol, compliance levels could at least be monitored, Tremblay said. Giving parents a diet logbook would help with compliance, Sweeney agreed.

Uncontrolled diets in the trial would lead to weight gain across both arms, Tremblay said. This could in turn compromise patients’ ability to walk and perform functional tests, thus negatively affecting the results of the trial’s other primary and secondary functional endpoints, he said. Muscle function measured by TTSTAND is a primary endpoint whereas efficacy as measured by the time to Run/Walk Test (TTRW) and North Star Ambulatory Assessment (NSAA) is included in the secondary endpoints.

However, even if diets are uncontrolled in the trial, body size results across the arms would still be a fair comparison as children within the enrolled age range tend to eat varied diets anyway, said Dr Barry Byrne, associate chair, Department of Pediatrics, University of Florida College of Medicine, Gainesville.

The trial diet remains uncontrolled in order to observe whether, under conditions reflecting routine clinical care where there is no defined diet, prevalent weight gain would still be observed with vamorolone, the spokesperson said. Besides, regulators did not require the implementation of a standard diet, the spokesperson added.

The rationale behind measuring body size is that one of prednisone’s early side effects is excessive weight gain, Sweeney explained. However, weight gain on prednisone is patient-variable and can be avoided if parents control a child’s diet, he added. If prednisone leads to more weight gain on the Phase IIb trial due to parents not controlling their children’s diets, this could bias data in favour of Santhera Pharmaceuticals’ vamorolone, Sweeney noted. Body size is not a common endpoint in DMD studies so it is difficult to tout benchmarks for clinical significance, Byrne said.

Risk-benefit profile appears to imitate a weak steroid

With regard to the 48-patient, nonrandomised Phase IIa extension trial (NCT02760277) data, in a DMD population where there is a risk of decline in function, any improvement is meaningful, said Byrne. In the trial’s coprimary endpoint of TTSTAND mean velocity change from baseline to week 24, the mean change for the 2.0 mg/kg/d group was significant when compared to the untreated cohort, with a p-value of 0.04 (Hoffman, E et al. Neurology. September 24, 2019; 93:13). The change was also significant for the comparison of the 2.0 and 6.0 mg/kg/d groups to the 0.25 mg/kg/d group, with p-values of 0.02 and 0.04, respectively.

The data seem positive for both the 2.0 and 6.0 mg/kg/d groups, also studied in the Phase IIb, but a lengthier follow-up is required to determine the long-term efficacy of vamorolone over three to four years, Tremblay said. That could then judge clinical meaningfulness, he said. It is difficult to form a definitive conclusion about treatment efficacy given the earliness of the data, Sweeney agreed. The results suggest that efficacy can be observed at higher doses but is somewhat compromised at lower doses, Sweeney explained, adding higher doses bring more safety events. In this way, vamorolone’s risk-benefit profile appears to imitate that of a steroid, just with lower overall intensity, Sweeney stated.

But the safety profile of Santhera Pharmaceuticals’ vamorolone thus far appears reasonable, said Kay Davies, PhD, professor of Genetics, University of Oxford, UK. The most common treatment-related adverse events observed in the Phase IIa trial extension period were respiratory tract infection (41.7%), pyrexia (35.8%), cough (18.8%) and vomiting (14.6%), according to the aforementioned article. These data seem better than the high level of side effects observed with some current corticosteroids, Davies explained, adding results from more patients are required to confirm safety.

However, these numbers seem higher than those associated with the use of Emflaza, Sweeney noted. Emflaza is associated with both upper respiratory tract infection and cough at 12% at 12 weeks post-treatment, according to its FDA label. But even so, when compared with the long-term association of steroids with growth issues and bone fragility, the vamorolone safety profile thus far seems preferable, Byrne said. It is important to focus safety analysis on side effects which are clearly associated with glucocorticoids and identified as limiting factors, such as weight gain, stunting of growth and elevated risk of bone fractures, the spokesperson said.

Ayisha Sharma is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.